P801: BASELINE AND EARLY POST-INFUSION BIOMARKERS ASSOCIATED WITH OPTIMAL RESPONSE TO IDECABTAGENE VICLEUCEL (IDE-CEL) IN THE KARMMA-3 STUDY OF TRIPLE-CLASS–EXPOSED RELAPSED AND REFRACTORY MULTIPLE MYELOMA
Authors: Julia Piasecki, Keyur Desai, Carolyn Courtney, Ethan Thompson, James Pratt, Noopur Raje, Krina Patel, Marc S. Raab, Mark Cook, Katy Simonsen, Mihaela Popa Mckiver, Shari Kaiser, Nathan Martin
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Ide-cel, a B-cell maturation antigen (BCMA) chimeric antigen receptor T cell therapy, significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in patients with triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM) in the KarMMa-3 study (NCT03651128; Rodríguez-Otero et al. NEJM 2023). Previous analyses in KarMMa (Munshi et al. NEJM 2021) of patients with later-line (4L+) TCE RRMM identified low baseline levels and complete clearance of soluble BCMA (sBCMA, a measure of tumor burden) and early minimal residual disease (MRD) negativity as correlates of durable response to ide-cel. Aims: The current analysis explored the association between biomarkers and efficacy or severity of inflammatory adverse events of ide-cel in KarMMa-3. Methods: sBCMA levels were measured in blood samples collected from patients in KarMMa-3 at baseline and at regular intervals from treatment initiation until confirmed progression. MRD status was assessed in bone marrow aspirate (clonoSeq®; 10-5 sensitivity) at 6 and 12 months post infusion and reported in all patients, regardless of response. Biomarker analyses were based on patients who received ide-cel or ≥1 dose of standard regimen. Post hoc analyses assessed correlations between biomarkers and efficacy endpoints or cytokine release syndrome (CRS) and investigator-identified neurotoxicity (iiNT); associations of interest were identified using a ranked sum test and nominal P value <0.05. Results: Lower baseline sBCMA levels were associated with higher ORR (< partial response [PR] vs ≥PR) in both treatment arms (ide-cel, P=0.0223; standard regimens, P=0.0395), indicating this may be agnostic of the BCMA-directed modality. Lower baseline sBCMA was also associated with higher complete response (CR) rate (<CR vs ≥CR) in the ide-cel arm (P=0.0038). Additionally, lower baseline sBCMA levels in the ide-cel arm were associated with lower grade of CRS (grade 0–1 vs 2 vs ≥3; P=0.0022) and iiNT (grade 0–1 vs ≥2; P=0.0113); however, overlapping ranges may limit predictive utility. Further analyses will be presented. In the ide-cel arm, landmark median PFS was longer in patients with undetectable versus detectable sBCMA at 2 months post infusion (16.3 vs 5.2 months; HR, 0.26) or at 6 months (16.8 vs 9.6 months; HR, 0.62). Furthermore, landmark median PFS was also longer in patients with MRD negativity versus patients with positive/indeterminate MRD status at 6 months (17.2 vs 5.8 months; HR, 0.288) or at 12 months (13.8 vs 4.6 months; HR, 0.121). Summary/Conclusion: Baseline sBCMA levels correlated with response and grade of CRS and iiNT in the ide-cel arm of KarMMa-3, potentially reinforcing the importance of management of baseline tumor burden for optimal response to ide-cel. Early clearance of sBCMA at 2 months, sustained clearance of sBCMA at 6 months, and MRD negativity at 6 or 12 months, regardless of clinical response, may be useful biomarkers for identifying patients likely to achieve a complete and durable response to ide-cel. Keywords: Clinical trial, CAR-T, Multiple myeloma, B-cell maturation antigen